期刊
NATURE METABOLISM
卷 2, 期 12, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s42255-020-00314-2
关键词
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资金
- National Institutes of Health (NIH) [R01DK113185, R01HG009658]
- Mt. Sinai Health Care Foundation [OSA510114, OSA510113]
- Clinical and Translational Science Collaborative at Case Western Reserve University [VSN639001]
- NIH MSTP training grant [T32 GM007250]
- Functional Genomics Training Program grant [T32 GM135081]
The in vitro differentiation of insulin-producing beta-like cells can model aspects of human pancreatic development. Here, we generate 95,308 single-cell transcriptomes and reconstruct a lineage tree of the entire differentiation process from human embryonic stem cells to beta-like cells to study temporally regulated genes during differentiation. We identify so-called 'switch genes' at the branch point of endocrine/non-endocrine cell fate choice, revealing insights into the mechanisms of differentiation-promoting reagents, such as NOTCH and ROCKII inhibitors, and providing improved differentiation protocols. Over 20% of all detectable genes are activated multiple times during differentiation, even though their enhancer activation is usually unimodal, indicating extensive gene reuse driven by different enhancers. We also identify a stage-specific enhancer at the TCF7L2 locus for diabetes, uncovered by genome-wide association studies, that drives a transient wave of gene expression in pancreatic progenitors. Finally, we develop a web app to visualize gene expression on the lineage tree, providing a comprehensive single-cell data resource for researchers studying islet biology and diabetes. By using single-cell transcriptomics, Weng et al. reveal complex temporal gene control during pancreatic beta-cell differentiation from human embryonic stem cells, allowing for the construction of a unique lineage tree and optimization of differentiation protocols.
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